Strategies to prevent oral HIV-1 transmission are needed immediately. Mother-to-child transmission of HIV-1 accounts for about 700,000 new HIV-1 infections in children every year, many of them via breast-feeding. To reduce the incidence of pediatric HIV-1 infections, a better understanding of mechanisms of oral transmission and mucosal host immune responses in infants is needed. The rhesus macaque model of SIV infection provides us with a model to study innate and adaptive host immune responses induced locally and systemically after oral SIV infection and to correlate these responses with virus replication and disease progression. Type I interferon responses are critical in antiviral immunity as they serve two functions: they exert direct antiviral effects via interferon-stimulated genes (ISG's), and type I interferon responses are essential for the induction of antiviral T and B cell responses. Despite their potential key role in anti-HIV immunity, type I interferon responses have not been defined at mucosal entry sites for HIV. Thus, this study proposes to examine the role of local type I interferon responses in anti-SIV immunity after oral SIV infection in infant and juvenile macaques. The hypothesis to be tested is that infant macaques have a higher susceptibility to oral SIV infection and show faster disease progression compared to juvenile macaques due to their inability to elicit effective antiviral type I interferon responses in the oral mucosa. Aim 1 of the proposal will define the organization and functional capacity of the type I interferon system in the oral mucosa of healthy infant and juvenile macaques to determine if there are age-related differences in the ability to mount type I interferon responses. AIM 2 will define the in-vivo type I interferon response to oral SIV challenge in the oral mucosa of infant and juvenile macaques using multiple genomic, immunohistochemical and immunological approaches. The results of the proposed study should greatly enhance our understanding of innate antiviral immune responses induced in the oral mucosa of SIV infected macaques and, thus, will have important implications for the design of immunomodulatory interventions aimed at reducing oral HIV transmission. [unreadable] [unreadable]